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B.C. researchers discover mutation that causes worst form of MS

Author of the article:

Randy Shore

Publishing date:

June 1, 2016 • 3 minute read

Carles Vilarino-Guell, a professor of medical genetics at UBC and a member of the Djavad Mowafaghian Centre for Brain Health, is on a team of researchers that have identified a gene mutation that causes the worst form of MS. [PNG Merlin Archive]ubc handout/ PNG

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Researchers in B.C. have discovered a single gene mutation that leads to rapidly progressive multiple sclerosis, revealing for the first time a root cause of the most devastating form of the disease.

In the near term, the discovery should allow much earlier diagnosis and the opportunity to pursue more aggressive treatment of people who have the mutation, perhaps before symptoms even appear, said co-author Tony Traboulsee, a professor and research chair of the MS Society of Canada at the University of British Columbia.

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Once symptoms appear, there is no effective treatment available for the progressive form of the disease, which represents about 15 per cent of all cases.

“This (discovery) could give us a critical early window of opportunity to throw everything at the disease, to try to stop it or slow it,” he said. “Until now, we didn’t have much basis for doing that.”

More importantly, scientists now have a clear target for drugs that might produce a cure for up to half of people with MS, said senior author Carles Vilarino-Guell, a professor of medical genetics at UBC and a member of the Djavad Mowafaghian Centre for Brain Health.

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MS is an immune-mediated disease in which the body’s natural defences attack the myelin insulation on neurons in the brain. When myelin is damaged the brain’s communications are impaired leading to poor coordination, visual problems, muscle weakness and disrupted memory and thought processes.

The mutation discovered on the NR1H3 gene causes the production of a defective protein which regulates other genes that prevent inflammation and control myelin repair.

“This is like a lighthouse pointing to important mechanisms in cells that lead to multiple sclerosis,” said Vilarino-Guell. “In addition to this rare mutation, there are other variations on the same gene that are risk factors for the disease.”

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The defective protein made by the mutated gene disrupts a long chain of downstream processes that lead to the destruction of myelin, a series of reactions central to the progress of the disease in about 50 per cent of MS cases.

“If we develop a treatment that works for people with the newly discovered mutation it is likely to help people whose illness is affected by that same biological pathway,” he said.

Nearly 70 per cent of people with the newly discovered mutation will develop rapidly progressive MS in which symptoms become steadily worse without remission. Until now, the most potent genetic mutation associated with the disease increased the risk of MS by only three per cent.

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Long thought to be caused by environmental influences, advances in genetic analysis have only recently shed light on the genetic component of multiple sclerosis.

“Thinking on the causes of MS has been a mixed bag of everything, including a lot of genetic components that have very limited effects and a variety of environmental causes,” said Vilarino-Guell. “But in some families there is a single mutation responsible for MS and if you have it, it’s almost guaranteed you are going to develop the disease.”

By sequencing the genes in DNA samples taken from 2,000 Canadian families affected by MS, the researchers found two families that share this specific mutation.

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The DNA samples were collected over a 20-year period by UBC neurologist and study co-author Dessa Sadovnick, despite the objections of many scientists — including her own PhD thesis adviser who tried to convince her to abandon the search for genetic causes.

“People thought I was nuts,” said Sadovnick. “Back then, genetics was mostly focused on birth defects. Adult disorders were not thought of in terms of genetics. But I’m a sucker.”

The discovery of a potent single mutation is a vindication of her work, said Vilarino-Guell.

“It has been infuriating to have people tell us we are never going to find anything because MS is not a genetic disease,” he said. “The biobank that Dessa Sadovnick created has been key to finding heritable forms.”

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The discovery also represents a big leg up for future research in animal models, which until now were not able to replicate the biological reactions that lead to MS in humans.

Researchers had been injecting mice with myelin to trigger immune reactions or feeding them drugs that destroy myelin, neither of which resembles the actual progress of the disease.

Mice genetically engineered to have the mutation are already on order, which the researchers believe can be used for rapid testing of candidate drugs before they are tested on human patients.

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